Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10

Significance Allergic asthma represents an increasingly common public health problem. Here, we provide preclinical evidence for the efficacy of active tolerization using Helicobacter pylori components as a viable strategy for asthma prevention. We use a mouse model of allergic asthma to show that regular treatment with H. pylori extract effectively alleviates all hallmarks of the disease. Successful treatment depends on the regulatory cytokine IL-10 and on basic leucine zipper ATF-like 3 (BATF3)-dependent dendritic cell lineages. H. pylori extracts lacking the γ-glutamyl-transpeptidase GGT or the vacuolating cytotoxin VacA fail to protect against asthma; conversely, both factors can be administered in purified form to achieve protection. In conclusion, the immunomodulatory properties of the common infectious agent H. pylori can be exploited for therapeutic purposes in an allergy model. The prevalence of allergic asthma and other atopic diseases has reached epidemic proportions in large parts of the developed world. The gradual loss of the human indigenous microbiota has been held responsible for this trend. The bacterial pathogen Helicobacter pylori is a constituent of the normal gastric microbiota whose presence has been inversely linked to allergy and asthma in humans and experimental models. Here we show that oral or i.p. tolerization with H. pylori extract prevents the airway hyperresponsiveness, bronchoalveolar eosinophilia, pulmonary inflammation, and Th2 cytokine production that are hallmarks of allergen-induced asthma in mice. Asthma protection is not conferred by extracts from other enteropathogens and requires a heat-sensitive H. pylori component and the DC-intrinsic production of IL-10. The basic leucine zipper ATF-like 3 (BATF3)-dependent CD103+CD11b− dendritic cell lineage is enriched in the lungs of protected mice and strictly required for protection. Two H. pylori persistence determinants, the γ-glutamyl-transpeptidase GGT and the vacuolating cytotoxin VacA, are required and sufficient for asthma protection and can be administered in purified form to prevent asthma. In conclusion, we provide preclinical evidence for the concept that the immunomodulatory properties of H. pylori can be exploited for tolerization strategies aiming to prevent allergen-induced asthma.